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Factors that influence treatment delay in

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Article in Oncotarget December 2016

DOI: 10.18632/oncotarget.13574

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Factors that influence treatment delay in patients with colorectal

cancer
Irene Zarcos-Pedrinaci1,11, Alberto Fernndez-Lpez2, Teresa Tllez1,11, Francisco
Rivas-Ruiz1,11, Antonio Rueda A3,11, Mara Manuela Morales Suarez-Varela4,
Eduardo Briones5, Marisa Bar6,11, Antonio Escobar7,11, Cristina Sarasqueta8,11,
Nerea Fernndez de Larrea9,11, Urko Aguirre10,11, Jos Mara Quintana10,11, Maximino
Redondo1,11, on behalf of the CARESS-CCR Study Group
1
Research Unit, Agencia Sanitaria Costa del Sol, Marbella, Spain
2
Servicio de Ciruga, Agencia Sanitaria Costa del Sol, Marbella, Spain
3
Servicio de Oncologa Mdica, Agencia Sanitaria Costa del Sol, Marbella, Spain
4
Unit of Public Health, Hygiene and Environmental Health, Department of Preventive Medicine and Public Health, Food Science,
Toxicology and Legal Medicine, University of Valencia, CIBER-Epidemiology and Public Health (CIBERESP), Valencia, Spain
5
Public Health Unit, Distrito Sanitario Sevilla, Consorcio de Investigacin Biomdica de Epidemiologa y Salud Pblica,
Madrid, Spain
6
Clinical Epidemiology and Cancer Screening, Corporaci Sanitria Parc Taul, Sabadell, Spain
7
Research Unit, Hospital Universitario Basurto, Bilbao, Spain
8
Research Unit, Donostia University Hospital, San Sebastin, Spain
9
Area of Environmental Epidemiology and Cancer, National Epidemiology Centre, Instituto de Salud Carlos III, Consortium
for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiologa y Salud Pblica, CIBERESP), Madrid, Spain
10
Research Unit, Hospital Galdakao-Usansolo, Galdakao, Spain
11
Red de Investigacin en Servicios de Salud en Enfermedades Crnicas REDISSEC, Spain
Correspondence to: Maximino Redondo, email: mredondo@hcs.es
Keywords: Colorectal, cancer, delay, treatment, education
Received: May 30, 2016 Accepted: November 12, 2016 Published: November 24, 2016

ABSTRACT

A prospective study was performed of patients diagnosed with colorectal cancer

(CRC), distinguishing between colonic and rectal location, to determine the factors
that may provoke a delay in the first treatment (DFT) provided.
2749 patients diagnosed with CRC were studied. The study population was
recruited between June 2010 and December 2012. DFT is defined as time elapsed
between diagnosis and first treatment exceeding 30 days.
Excessive treatment delay was recorded in 65.5% of the cases, and was more
prevalent among rectal cancer patients. Independent predictor variables of DFT
in colon cancer patients were a low level of education, small tumour, ex-smoker,
asymptomatic at diagnosis and following the application of screening. Among rectal
cancer patients, the corresponding factors were primary school education and being
asymptomatic.
We conclude that treatment delay in CRC patients is affected not only by
clinicopathological factors, but also by sociocultural ones. Greater attention should
be paid by the healthcare provider to social groups with less formal education, in
order to optimise treatment attention.

INTRODUCTION is the second most prevalent malignancy worldwide, and is

also second in incidence and mortality in most developed
Colorectal cancer (CRC) is a major public health countries. In Europe, five-year survival rates are 44-64%,
problem, with major impact on morbidity and mortality. It and in Spain the EUROCARE-4 project calculated a

www.impactjournals.com/oncotarget 1 Oncotarget
 survival rate of 61.5% [1]. As a result of population aging,
together with diagnostic and therapeutic advances, the
number of cancer patients has increased significantly, and
this situation is placing great pressure on the cancer care
system, reflecting the growing importance of this group of
diseases as a public health problem.
Early diagnosis of cancer and hence early treatment
is a fundamental objective in cancer care procedures.
Although delays attributable to the health system
constitute a small proportion of the biological life of a
tumour, noticeable hospital delay (from first hospital visit
to diagnosis or from diagnosis to treatment) may provoke
stress and decrease the patients quality of life. In fact,
delays in initiating treatment are the leading cause of
malpractice complaints [2].
While some studies indicate that treatment delay
negatively affects the prognosis of patients with cancer,
particularly CRC, others have found no such association
[3, 4]. Moreover, it has been reported that delay is often
attributable to tumour factors such as clinical stage and
location, and not only to the health system, such as
hospital admission procedures. The impact of treatment
delay on survival, and the significance of the diverse
factors involved, have yet to be determined [5]. Waiting
time is a complex variable, which can reflect the patients
own behaviour, the clinical course, the functioning of the
health system and tumour biology [6].
Taking into account the dearth of prospective studies
designed to analyse treatment delay, with large cohorts of
patients and distinguishing between colonic and rectal
tumours, in this study we evaluate the degree to which
treatment delay is influenced by the sociodemographic
conditions of patients and by the clinical and pathological
characteristics of the tumour.
RESULTS
Descriptive analysis
During the recruitment period, the 22 participating
centres recruited 2,749 patients who met the criteria
for inclusion. Of these, 330 (12%) were later excluded
from the study because it was not possible to determine
the treatment delay. Thus, the final patient sample was
composed of 2,419 records. The sociodemographic and
clinicopathological characteristics of the study population
are shown in Table 1.
Treatment delays and types of treatment
For all tumours, the most common initial treatment
was surgery (81.4%), followed by chemotherapy
(13%) (p<0.001). For rectal tumours alone, surgery and
chemotherapy were also the most common treatment
options (40.5% and 39.5%, respectively).
www.impactjournals.com/oncotarget
A histogram showing the distribution of treatment
delay is shown in Figure 1. A delay to first treatment
exceeding 30 days was recorded in 65.5% of cases [95%
CI: 63.6-67.4], and this value was higher (p<0.001) for
rectal tumours (74.4%) than for colon tumours (62.2%)
(Table 2). Stratifying according to the first mode of
treatment administered and by tumour location, there
was a higher frequency of delay for surgical treatment for
rectal tumours than for colon tumours (79.2% vs. 62.2%)
(p<0.001). No significant differences were observed for
the other treatment strategies.
Relation between treatment delay and
the patients sociodemographic and
clinicopathological characteristics
In our analysis of the relation between the presence
of DFT and each of the sociodemographic variables,
those that were significantly associated with greater
DFT in patients with cancer of the colon were male sex,
low level of education or no formal education, BMI
(285.1), ex-smoker and asymptomatic at diagnosis. The
most relevant tumour characteristics were small local
extension and the absence of nodes, of metastasis and
of perineural invasion. Treatment delays in patients with
tumours presenting normal values for carcinoembryonic
antigen and for cancer antigen 19-9 were greater than
among patients presenting abnormal values for these
parameters. Finally, the treatment delay in patients who
had received prior screening was greater than among
those who had not had this test (Table 3). For rectal
tumours, the variables that were significantly related to
a higher level of DFT were primary studies or no formal
education, being asymptomatic and having had prior
screening (Table 4).
After adjusting for variables found to be statistically
significant in the crude analysis, the multivariate analysis
revealed the following to be independent protective factors
against increased DFT: having university studies, for colon
cancer [OR = 0.69; 95% CI 0.52-0.91] and for rectal cancer
[OR = 0.56; 95% CI 0.34-0.91]; later tumour stage, for
colon tumours, T3-T4, [OR = 0.51; 95% CI 0.37-0.69];
and for rectal tumours, the presence of severe [OR = 0.31;
95% CI 0.09-1.07] or moderate symptoms [OR = 0.67;
95% CI 0.16-2.74], compared with asymptomatic patients.
However, DFT was greater in the patients with colon cancer
who were ex-smokers [OR = 1.40; 95% CI 1.09-1.80] and
in those who had had prior screening [OR = 1.79; 95% CI:
1.32-2.43] (Tables 3 and 4).
DISCUSSION
Our study highlights the existence of delayed
implementation of the first treatment among 65.5% of the
2 Oncotarget
 Table 1: Sociodemographic and clinical characteristics for all cases and segmented by type of tumour
Total Colon Rectal p
n % n % n %
Sex
Male 1539 63.6 1092 62.2 447 67.3 0.023
Female 880 36.4 663 37.8 217 32.7
Age
Mean - SD 68.3 10.9 68.8 10.8 66.9 11.0 <0.001
Marital status1

Single 150 7.6 100 6.9 50 9.1 0.048

Married-Cohabiting 1434 72.2 1028 71.4 406 74.2
Separated-Divorced 100 5.0 76 5.3 24 4.4
Widowed 302 15.2 235 16.3 67 12.2
Education profile 2

No education-Primary
1531 77.2 1114 77.1 417 77.2 1.000
education
Secondary-University 453 22.8 330 22.9 123 22.8
Currently in work 3

No 1493 76.3 1072 75.3 421 78.7 0.135

Yes 465 23.7 351 24.7 114 21.3
BMI4
Mean - SD 27.7 4.8 28.0 4.9 27.1 4.5 <0.001
Smoking habit 5

Never 1109 47.8 831 49.6 278 43.3 0.008

Current smoker 302 13.0 201 12.0 101 15.7
Ex-smoker 908 39.2 645 38.5 263 41.0
Family history of neoplasias 6

No 1339 61.3 990 63.1 349 56.7 0.007

Yes 846 38.7 580 36.9 266 43.3
Family history of CRC 7

No 1295 86.2 934 86.3 361 85.7 0.837

Yes 208 13.8 148 13.7 60 14.3
Specific signs and symptoms8
Asymptomatic 204 8.8 160 9.6 44 6.9 <0.001
Moderate signs and symptoms 381 16.5 300 18.0 81 12.6
Severe signs and symptoms 1724 74.7 1207 72.4 517 80.5
Type of tumour
Colon 1755 72.6
Recto 664 27.4
(Continued)

www.impactjournals.com/oncotarget 3 Oncotarget
 Total Colon Rectal p
n % n % n %
Size of tumour9
Locally small (T0-T1-T2) 681 28.8 376 21.9 305 47.0 <0.001
Locally large (T3-T4) 1686 71.2 1342 78.1 344 53.0
Lymph nodes10
Absent 1464 62.7 1028 60.0 436 70.1 <0.001
Present 871 37.3 685 40.0 186 29.9
Histological diagnosis 11

Adenocarcinoma 2152 89.6 1555 89.0 597 91.3 0.121

Mucinous carcinoma or other
249 10.4 192 11.0 57 8.7
types
Metastasis12
Absent 2057 91.9 1483 91.2 574 93.8 0.056
Present 181 8.1 143 8.8 38 6.2
Differentiation13
Low grade 1790 86.9 1333 86.4 457 88.2 0.336
High grade 270 13.1 209 13.6 61 11.8
Vascular invasion 14

Absent 1764 86.4 1259 84.4 505 92.0 <0.001

Present 277 13.6 233 15.6 44 8.0
Perineural invasion 15

Absent 1627 81.4 1165 80.1 462 84.8 0.019

Present 373 18.7 290 19.9 83 15.2
Carcinoembryonic antigen (CEA)16
Normal (0-5) 1328 68.7 917 67.5 411 71.6 0.083
Abnormal (>5) 605 31.3 442 32.5 163 28.4
Cancer antigen 19-917
Normal (1-37) 944 85.4 620 84.1 324 88.0 0.099
Abnormal (>37) 161 14.6 117 15.9 44 12.0
Prior screening 18

No 1868 80.8 1330 79.1 538 85.4 0.001

Yes 443 19.2 351 20.9 92 14.6

Losses: 1=433; 2=435; 3=461; 4=552; 5=100; 6=234; 7=916; 8=110.

Losses: 9=52; 10=84; 11=18; 12=181; 13=359; 14=378; 15=419; 16=486; 17=1314; 18=108

population diagnosed with CRC. This finding lies within the
40-70% range of treatment delay previously reported [7].
Studies have been conducted to evaluate the
prognostic influence of diagnostic and treatment delays
on different types of cancer, and to determine the
significant factors in this process. However, conflicting
results have been obtained, due in part to differences
in the characteristics of the populations analysed;
furthermore, in most cases, the cohorts have been
examined retrospectively and there have been differences
in the time intervals studied [8]. This is a controversial
issue, and it remains to be clarified. Unlike these earlier

www.impactjournals.com/oncotarget 4 Oncotarget
 studies, our own research is based on a large number of
patients recruited prospectively. We define excessive delay
between diagnosis and treatment as a period exceeding
30 days, following previous recommendations and reports
in this respect [9, 10, 11, 12, 13]
Unlike other studies on diagnostic and treatment
delays in patients with CRC, our study population is
distributed according to the location of the tumour (colon
or rectal), in view of the well-known differences in the
pathogenesis of each. We found DFT to be significantly
greater for rectal tumours, as was also reported in the
case of delay attributable to the patient [14]. Analysis of
the delay according to the type of first treatment applied
showed that this difference persisted when the first
treatment was surgery, but not when it was chemotherapy
or radiotherapy. This association is consistent with the
findings of other studies, which have related the delay
in surgical treatment for advanced stage (according to
the Dukes system) rectal tumours, but not for tumours of
the colon [15], probably because in localised and locally-
Figure 1: Frequency histogram of delay (in days) to first treatment for patients with CRC.
www.impactjournals.com/oncotarget
advanced rectal tumours, and unlike for colon cancer, other
diagnostic tests are required prior to treatment, such as
pelvic magnetic resonance imaging and rectal endoscopic
ultrasound examination [16]. Another difference between
the two types of cancer was the relationship between DFT
and the digestive symptoms diagnosed; a shorter DFT was
only observed in patients with rectal cancer and moderate
to severe symptoms, compared with mildly symptomatic
or asymptomatic patients. Possibly the more pronounced
and alarming symptoms resulting from rectal tumours,
i.e. bleeding and pain, compared to the less specific and
subacute ones provoked by colon tumours, lead patients
with rectal cancer to seek a medical consultation at an
earlier stage, thus expediting the diagnostic-therapeutic
circuit. The physician prescribing the treatment will
probably give preference to symptomatic patients, who
are at increased risk of presenting complications from
the tumour and therefore have a worse prognosis. It
should also be taken into account that some patients with
advanced tumours do not state the actual date of onset of
5 Oncotarget
 Table 2: Type of first treatment and delays
Total Colon Rectal p
n % n % n %
First line of treatment
Surgery 1968 81.4 1699 96.8 269 40.5 <0.001
Chemotherapy1 314 13.0 52 3.0 262 39.5
Radiotherapy 137 5.7 4 0.2 133 20.0
Delay in first treatment
30 days 834 34.5 664 37.8 170 25.6 <0.001
>30 days 1585 65.5 1091 62.2 494 74.4
Delay before surgery
30 days 699 35.5 643 37.8 56 20.8 <0.001
>30 days 1269 64.5 1056 62.2 213 79.2
Delay before chemotherapy
30 days 96 30.6 20 38.5 76 29.0 0.235
>30 days 218 69.4 32 61.5 186 71.0
Delay before radiotherapy
30 days 39 28.5 1 25.0 38 28.6 1.000
>30 days 98 71.5 3 75.0 95 71.4
1
With or without radiotherapy

Table 3: Bivariate and multivariate analysis with DFT in patients with colon cancer
30 days >30 days Crude analysis Adjusted analysis*
n % n % p OR 95% CI p OR 95% CI
Sex
Male 393 36.0 699 64.0 0.041 1.00
Female 271 40.9 392 59.1 0.81 [0.67-0.99]
Age
Mean - SD 68.8 11.3 68.8 10.4 0.915 1.00 [0.99-1.01]
Marital status
Single 38 38.0 62 62.0 0.182 1.00
Married-Cohabiting 374 36.4 654 63.6 1.07 [0.70-1.64]
Separated-Divorced 21 27.6 55 72.4 1.60 [0.84-3.06]
Widowed 97 41.3 138 58.7 0.87 [0.54-1.41]
Education profile
No education-
388 34.8 726 65.2 0.001 1.00 0.008 1.00
Primary education
Secondary-
148 44.8 182 55.2 0.66 [0.51-0.84] 0.69[0.52-0.91]
University

(Continued)

www.impactjournals.com/oncotarget 6 Oncotarget
 30 days >30 days Crude analysis Adjusted analysis*
n % n % p OR 95% CI p OR 95% CI
Currently in work
No 396 36.9 676 63.1 0.482 1.00
Yes 137 39.0 214 61.0 0.91 [0.71-1.17]
BMI
Mean - SD 27.2 4.4 28.4 5.1 <0.001 1.06 [1.03-1.08]
Smoking habit
Never 332 40.0 499 60.0 0.017 1.00 0.028 1.00
Current smoker 83 41.3 118 58.7 0.95 [0.69-1.29] 1.08[0.74-1.57]
Ex-smoker 215 33.3 430 66.7 1.33 [1.07-1.65] 1.40[1.09-1.80]
Family history of neoplasias
No 374 37.8 616 62.2 0.952 1.00
Yes 220 37.9 360 62.1 0.99[0.80-1.23]
Family history of CRC
No 323 34.6 611 65.4 0.212 1.00
Yes 59 39.9 89 60.1 0.80[0.56-1.14]
Specific signs and symptoms
Asymptomatic 40 25.0 120 75.0 <0.001 1.00
Moderate signs and
132 44.0 168 56.0 0.42[0.28-0.65]
symptoms
Severe signs and
466 38.6 741 61.4 0.53[0.36-0.77]
symptoms
Size of tumour
Locally small (T0-
96 25.5 280 74.5 <0.001 1.00 <0.001 1.00
T1-T2)
Locally large (T3-T4) 555 41.4 787 58.6 0.49[0.37-0.63] 0.51[0.37-0.69]
Lymph nodes
Absent 365 35.5 663 64.5 0.015 1.00
Present 283 41.3 402 58.7 0.78[0.64-0.95]
Histological diagnosis
Adenocarcinoma 585 37.6 970 62.4 0.597 1.00
Mucinous
76 39.6 116 60.4 0.92[0.68-1.25]
carcinoma
Metastasis
Absent 523 35.3 960 64.7 0.037 1.00
Present 63 44.1 80 55.9 0.69[0.49-0.98]
Differentiation
Low grade 490 36.8 843 63.2 0.223 1.00
High grade 86 41.1 123 58.9 0.83[0.62-1.12]

(Continued)
www.impactjournals.com/oncotarget 7 Oncotarget
 30 days >30 days Crude analysis Adjusted analysis*
n % n % p OR 95% CI p OR 95% CI
Vascular invasion
Absent 475 37.7 784 62.3 0.212 1.00
Present 98 42.1 135 57.9 0.83[0.63-1.11]
Perineural invasion
Absent 426 36.6 739 63.4 0.001 1.00
Present 137 47.2 153 52.8 0.64[0.50-0.83]
Carcinoembryonic antigen (CEA)
Normal (0-5) 324 35.3 593 64.7 0.010 1.00
Abnormal (>5) 188 42.5 254 57.5 0.74[0.58-0.93]
Cancer antigen 19-9
Normal (1-37) 219 35.3 401 64.7 0.011 1.00
Abnormal (>37) 56 47.9 61 52.1 0.59[0.40-0.89]
Prior screening
No 547 41.1 783 58.9 <0.001 1.00 <0.001 1.00
Yes 89 25.4 262 74.6 2.06[1.59-2.68] 1.79[1.32-2.43]
First line of treatment
Surgery 643 37.8 1056 62.2 0.869 1.00
Chemotherapy 20 38.5 32 61.5 0.97[0.55-1.72]
Radiotherapy 1 25.0 3 75.0 1.83[0.19-17.6]

* In multivariate logistic regression with a sample of 1,291 patients

Table 4: Bivariate and multivariate analysis with DFT in patients with rectal cancer
30 days >30 days Crude analysis Adjusted analysis*
n % p OR p OR p OR
95% CI 95% CI 95% CI
Sex
Male 109 24.4 338 75.6 0.303 1.00
Female 61 28.1 156 71.9 0.82[0.57-1.19]
Age
Mean - SD 65.9 11.2 67.2 11.0 0.168 1.01[0.99-1.03]
Marital status
Single 9 18.0 41 82.0 0.145 1.00
Married-Cohabiting 111 27.3 295 72.7 0.58[0.27-1.24]
Separated-Divorced 2 8.3 22 91.7 2.41[0.48-12.17]
Widowed 18 26.9 49 73.1 0.60[0.24-1.47]
Education profile
No education-Primary
97 23.3 320 76.7 0.025 1.00 0.020 1.00
education
(Continued)
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 30 days >30 days Crude analysis Adjusted analysis*
n % p OR p OR p OR
95% CI 95% CI 95% CI
Secondary-University 41 33.3 82 66.7 0.61[0.39-0.94] 0.56[0.34-0.91]
Currently in work
No 107 25.4 314 74.6 0.845 1.00
Yes 30 26.3 84 73.7 0.95[0.60-1.53]
BMI
Mean - SD 26.9 4.1 27.1 4.7 0.699 1.01[0.96-1.05]
Smoking habit
Never 71 25.5 207 74.5 0.989 1.00
Current smoker 26 25.7 75 74.3 0.99[0.59-1.67]
Ex-smoker 66 25.1 197 74.9 1.02[0.69-1.51]
Family history of neoplasias
No 88 25.2 261 74.8 0.757 1.00
Yes 70 26.3 196 73.7 0.94[0.66-1.36]
Family history of CRC
No 91 25.2 270 74.8 0.386 1.00
Yes 12 20.0 48 80.0 1.35[0.87-2.65]
Specific signs and symptoms
Asymptomatic 4 9.1 40 90.9 0.009 1.00 0.031 1.00
Moderate signs and
15 18.5 66 81.5 0.44[0.14-1.42] 0.67[0.16-2.74]
symptoms
Severe signs and
146 28.2 371 71.8 0.25(0.09-0.72) 0.31[0.09-1.07]
symptoms
Size of tumour
Locally small (T0-
78 25.6 227 74.4 0.998 1.00
T1-T2)
Locally large (T3-T4) 88 25.6 256 74.4 1.00[0.70-1.42]
Lymph nodes
Absent 116 26.6 320 73.4 0.292 1.00
Present 42 22.6 144 77.4 1.42[0.83-1.86]
Histological diagnosis
Adenocarcinoma 152 25.5 445 74.5 0.660 1.00
Mucinous carcinoma 13 22.8 44 77.2 1.16[0.61-2.20]
Metastasis
Absent 138 24.0 436 76.0 0.751 1.00
Present 10 26.3 28 73.7 0.89[0.42-1.87]
(Continued)

www.impactjournals.com/oncotarget 9 Oncotarget
 30 days >30 days Crude analysis Adjusted analysis*
n % p OR p OR p OR
95% CI 95% CI 95% CI
Differentiation
Low grade 106 23.2 351 76.8 0.175 1.00
High grade 19 31.1 42 68.9 0.67[0.37-1.20]
Vascular invasion
Absent 127 25.1 378 74.9 0.490 1.00
Present 9 20.5 35 79.5 1.31[0.61-2.79]
Perineural invasion
Absent 112 24.2 350 75.8 0.042 1.00 0.051 1.00
Present 29 34.9 54 65.1 0.60[0.36-0.98] 0.57[0.32-1.00]
Carcinoembryonic antigen (CEA)
Normal (0-5) 105 25.5 306 74.5 0.722 1.00
Abnormal (>5) 44 27.0 119 73.0 0.93[0.61-1.40]
Cancer antigen 19-9
Normal [137] 70 21.6 254 78.4 0.133 1.00
Abnormal [>37] 14 31.8 30 68.2 0.59[0.30-1.17]
Prior screening
No 148 27.5 390 72.5 0.025 1.00
Yes 15 16.3 77 83.7 1.95[1.09-3.49]
First line of treatment
Surgery 56 20.8 213 79.2 0.067 1.00
Chemotherapy 76 29.0 186 71.0 0.64[0.43-0.96]
Radiotherapy 38 28.6 95 71.4 0.66[0.41-1.06]

* In multivariate logistic regression with a sample of 433 patients

their symptoms, or minimise it, due to a feeling of guilt at
not having consulted the doctor sooner, and this too can
exacerbate the DFT [1719].
Studies of CRC have evaluated the relationship
between tumour stage and diagnostic and therapeutic
delays, and have found no association between these
parameters [20]. Although some studies have shown
that the DFT is shorter for patients presenting advanced
stages of the disease [21], others have concluded the
opposite [22]. Nevertheless, these conclusions cannot be
generalised for tumours of the colon and rectum as if they
were a single entity; on the contrary, they must be analysed
independently, in view of the different natural history
presented in each case [23, 24]. Thus, some retrospective
studies have shown that advanced rectal tumours present
an increased risk of DFT, in comparison with the initial
stages, while no such differences were found for cancers
of the colon [15]. On the other hand, in our own study,
tumour stages T1-T2 experienced greater DFT than more
advanced stages, but only in tumours of the colon. This
difference might arise from the lower priority assigned
to treatment for early-stage cancers, when symptoms
are usually less apparent and hence delay the start of
the therapeutic process. In a study of breast cancer, our
group evaluated the different periods of delay, noting that
higher tumour stages were associated with a shorter DFT,
which was associated with a lower disease-free survival
time. This outcome is probably produced by the priority
granted by doctors to patients whose symptoms are more
severe [6], which contradicts the traditional view that
greater delay is associated with decreased survival time.
This inverse correlation between treatment delay and
survival has been described previously in studies of the
endometrium and the lung [25, 26].
In our analysis of clinicopathological characteristics
with known prognostic value and associated with increased

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 tumour aggressiveness, the degree of histological
differentiation and of lymphovascular invasion presented
no relation to DFT. However, they were found to be
related to distant metastases, lymph node involvement,
perineural invasion and elevated tumour markers, all of
which decrease the risk of severe DFT. However, when a
multivariate analysis was performed, and other variables
were taken into account, these differences did not persist,
probably because the variables in question are more
dependent on the biological behaviour of the tumour
and on its intrinsic aggressiveness than on the period of
treatment delay, as suggested by Symonds in a study of
cervical cancer [27]. In other tumours, such as breast
cancer, a significant association has also been described
between the presence of more aggressive features and a
shorter delay in initiating treatment; such features may
include the non expression of hormone receptors, or
non response to hormonal treatments in tumours that do
express hormone receptors. These findings suggest that
treatment may be expedited when the physician is aware
of the extent of the tumour [6].
Among the sociocultural factors analysed, the
lack of formal education or only having had primary
education significantly increases the risk of DFT, for both
rectal and colon tumours. Interestingly, this association,
which has not received much previous research attention,
influences DFT independently of other factors. One
explanation for this might be that these patients do not
understand the instructions received during the diagnosis-
therapy process, and may also fail to keep the medical
appointments necessary for a definitive tumour treatment
to be undertaken. This population group, with a low
cultural level, might also delay the start of treatment for
fear of future treatments and distrust of the benefit derived
from them. This possibility was raised in a recent study
in which DFT was associated with a lack of knowledge
of symptoms suggestive of cancer, and with the patients
unwillingness to visit the doctor, among other factors
[28]. For these reasons, we believe that among certain
population groups, with unhealthy living habits and a low
educational profile, the risk of severe DFT is greater. In
this respect, a retrospective study was conducted to obtain
an ecological estimation of the socioeconomic status of
patients with cancer (European Deprivation Index). No
such relationship with DFT or with diagnostic delay was
found, although it should be noted that this study included
different types of cancer, with only 116 CRC [29].
Retrospective studies have evaluated social factors
that might influence treatment delay, noting that black
and/or elderly patients with rectal cancer were subject to
greatest delay in initiating adjuvant chemotherapy [30].
In another study, of bowel cancer [31], elderly and/or
unmarried patients were found to be most subject to this
delay. Other studies evaluating prehospital delay have also
found that lower socioeconomic level and lower education
level are relevant factors. [14, 32].
www.impactjournals.com/oncotarget
Another feature of our population which the
univariate analysis showed to be associated with increased
treatment delay was a high BMI (>28) in patients with
colon cancer. This relation would be explained, in part,
by the complication of abdominal examination in the
presence of a large pannus. One of the main causes of
obesity in the West is an unhealthy living habit in terms
of diet and exercise; this, too, is associated with a low
socio-cultural level, which as mentioned previously is an
independent predictor of treatment delay. The remaining
demographic variables analysedsex, age at diagnosis,
family history of cancer, marital status and occupation
bore no significant relation with DFT.
The relationship between treatment delay and ex-
smokers is a complex one. Elderly ex-smokers probably
have more limitations of the respiratory function and
require a larger number of tests before surgery. On the
other hand, a patient who gives up smoking will probably
believe him/herself at less risk of serious disease than a
continuing smoker, and this factor, too, may influence
communication with the doctor after diagnosis. In this
respect, Mosher et al., in a study of patients diagnosed
with lung cancer, reported that most ex-smokers rejected
psychological therapy [33].
Our results show that a prior positive screening,
in which faecal occult blood is detected, is associated
with a greater risk of treatment delay; this relation has
not been reported in previous studies. A priori, it seems
illogical that a patient who has received CRC screening
before any treatment is undertaken should suffer a delay
for this reason. However, probably due to the persons
asymptomatic state at the time of the consultation, no
preference is expressed (unlike the case of a patient with
manifest symptoms and at increased risk of complications
from the tumour, requiring prompt treatment).
Nevertheless, we considered the possible existence of
confounding and of interaction with the other variables,
and always obtained the same relationship between prior
screening and subsequent treatment delay. Neither were
there any interaction terms to be retained in the final
model (data not shown).
Although it has been shown that delayed diagnosis
and treatment does not appear to increase the risk of
death in patients with symptomatic CRC, among the
asymptomatic population early diagnosis and treatment
may play a role in reducing morbidity and mortality [34].
The results presented should be considered with caution,
and are subject to further analysis to determine whether,
in the screened population, the greater delay observed
impacts on survival.
The delay before cancer treatment is started is an
important factor to be evaluated. This delay, which is
a criterion of health care quality, should be prevented
and reduced as far as possible in order to avoid the
psychologically negative impact it may cause to patients.
Numerous studies have shown that treatment delay is
11 Oncotarget
 associated with certain clinical factors in CRC, but the
present study is the first to establish that DFT depends
not only on clinicopathological characteristics of the
tumour, or on deficiencies of the healthcare system, but
also on sociocultural characteristics of the population.
We conclude, therefore, that more attention should be
paid to health education regarding the initial symptoms
related to this disease, especially among less educated
social groups. The physician responsible for the patients
treatment, too, must be aware that these patients require
special attention.
Finally, more multicentre studies should be
conducted, in other countries and where different
healthcare plans are used, in order to generalise the
findings of our study. Another valuable area for future
research would be to determine whether treatment delay
also impacts on survival, as this association has not been
clarified in recent reviews of the question [6, 35].
MATERIALS AND METHOD
Study design
This prospective, multicentre observational study
was conducted in coordination with 22 public-sector
hospitals in six regions of Spain (Andalusia, Canary
Islands, Catalonia, Madrid, Valencia and the Basque
Country) [36].
The patients were recruited prospectively and
consecutively at each of the participating hospitals
between June 2010 and December 2012. The study
population included patients diagnosed with new colon or
rectum cancer, stage I-IV and surgically treated, whether
urgently or scheduled. All patients were included, whether
or not they had previously received treatment, and a follow
up study of five years was scheduled. Data were compiled
directly from patients and also from their medical history.
Study definitions
Excessive treatment delay was defined as an interval
exceeding 30 days from pathological diagnosis to first
treatment, in accordance with national guidelines and
previous reports [1013, 15]. First treatment was taken
to be surgery, chemotherapy, radiotherapy, biological
therapy or best supportive care. Date of diagnosis was
the date when histological confirmation of the process
was obtained, unless this coincided with the date of the
intervention. In this case, we used as first date of diagnosis
the suspected diagnosis [36].
The anatomical location of the tumour and the
histology findings were coded in accordance with the
International Classification for Oncology (ICD-O). Staging
classification was based on the TNM recommendations of
the International Union Against Cancer, 7th edition.
www.impactjournals.com/oncotarget
The following inclusion criteria were applied:
Patients diagnosed with cancer of the colon (up to
15 cm above the anal margin) or of the rectum (between the
anal margin and 15 cm above it), to which curative and/or
palliative surgical treatment was applied for the first time.
Signed informed consent provided.
The exclusion criteria were:
Patients diagnosed with cancer of the colon or
rectum in situ.
Unresectable tumours.
Mental or physical disorders that prevented the
patient from answering the questionnaires.
Terminal patients
The project was evaluated by the corresponding
Research Committees and Clinical Research Ethics
Committees at the hospitals. Informed consent was
requested of the patients before surgery. Current legislative
requirements regarding personal data (any information
concerning individuals who were identified or identifiable)
were followed at all times. All personal data were
processed in such a way that the information obtained
could not be associated with identified or identifiable
persons (Protection of Personal Data Act, 15/1999, 13-12).
Study variables
Data were compiled regarding the patients medical
history: Sex, age, body mass index, prior screening, date
of first contact with the hospital, first diagnosis, start of
treatment, and the various types of first treatment considered
(surgery, chemotherapy, radiotherapy, biological therapy or
best supportive care). The date of diagnosis was taken as
the date when the first histopathological report identifying
the presence of cancer, was issued, except patients treated at
the same time as they were diagnosed that we used as first
date of diagnosis the suspected diagnosis date. The following
laboratory and pathological factors were also recorded:
tumour location (rectum or colon), degree of histological
differentiation, tumour stage T and lymph node N (determined
by the TNM clinical staging system), lymphovascular and
perineural invasion, presence of metastasis, status of tumour
markers such as carbohydrate antigen (CA) 19-9 and serial
carcino-embryonic antigen (CEA). [37]
The following variables were self-reported by the
patient: family history of colorectal cancer and other
tumors, marital status, occupation at the time of the study,
education profile, smoking habit and symptoms prior to
surgery, date of onset of symptoms.
Statistical design
A descriptive analysis was performed, with measures
of central tendency and dispersion for the quantitative
variables and frequency distributions for the qualitative
12 Oncotarget
 ones. Differences were determined by bivariate analysis,
segmenting by type of tumour and by time elapsed to first
treatment, using the Student t test for quantitative variables
and the chi-square test for qualitative ones. Finally, the
treatment delay variable was used to perform a multivariate
logistic regression analysis, using the variables with a value
of p<0.1, together with the patients age and sex. The level
of statistical significance used in these analyses was p<0.05.
CARESS-CCR Study Group
Jose Mara Quintana Lpez1, Marisa Bar Maas2,
Maximino Redondo Bautista3, Eduardo Briones Prez
de la Blanca4, Nerea Fernndez de Larrea Baz5, Cristina
Sarasqueta Eizaguirre6, Antonio Escobar Martnez7,
Francisco Rivas Ruiz8, Maria M. Morales-Surez-Varela9,
Juan Antonio Blasco Amaro10, Isabel del Cura Gonzlez11,
Inmaculada Arostegui Madariaga12, Amaia Bilbao
Gonzlez7, Nerea Gonzlez Hernndez1, Susana Garca-
Gutirrez1, Iratxe Lafuente Guerrero1, Urko Aguirre
Larracoechea1, Miren Orive Calzada1, Josune Martin
Corral1, Ane Antn-Ladislao1, Nria Tor13, Marina Pont13,
Mara Purificacin Martnez del Prado14, Alberto Loizate
Totorikaguena15, Ignacio Zabalza Estvez16, Jos Errasti
Alustiza17, Antonio Z Gimeno Garca18, Santiago Lzaro
Aramburu19, Merc Comas Serrano20, Jose Mara Enrquez
Navascues21, Carlos Placer Galn21, Amaia Perales22, Iaki
Urkidi Valmaa23, Jose Mara Erro Azkrate24, Enrique
Cormenzana Lizarribar25, Adelaida Lacasta Muoa26, Pep
Piera Pibernat26, Elena Campano Cuevas27, Ana Isabel
Sotelo Gmez28, Segundo Gmez-Abril29, F. Medina-
Cano30, Antonio Rueda31, Julia Alcaide31, Arturo Del Rey-
Moreno32, Manuel Jess Alcntara33, Rafael Campo34,
Alex Casalots35, Carles Pericay36, Maria Jos Gil37, Miquel
Pera37, Pablo Collera38, Josep Alfons Espins39, Mercedes
Martnez40, Mireia Espallargues41, Caridad Almazn42,
Paula Dujovne Lindenbaum43, Jos Mara Fernndez-
Cebrin43, Roco Anula Fernndez44, Julio ngel Mayol
Martnez44, Ramn Cantero Cid45, Hctor Guadalajara
Labajo46, Mara Heras Garceau46, Damin Garca Olmo46,
Mariel Morey Montalvo47.
1. Unidad de Investigacin. Hospital Galdakao-
Usansolo, Galdakao-Bizkaia / Red de Investigacin
en Servicios de Salud en Enfermedades Crnicas
REDISSEC.
2. Epidemiologia Clnica y Cribado de Cancer,
Corporaci Sanitaria Parc Taul, Sabadell / Red de
Investigacin en Servicios de Salud en Enfermedades
Crnicas REDISSEC.
3. Servicio de Laboratorio. Hospital Costa del Sol,
Mlaga / REDISSEC.
4. Unidad de Epidemiologa. Distrito Sevilla,
Servicio Andaluz de Salud.
5. Area of Environmental Epidemiology and Cancer.
National Epidemiology Centre. Instituto de Salud Carlos
III. Consortium for Biomedical Research in Epidemiology
www.impactjournals.com/oncotarget
and Public Health (CIBER Epidemiologa y Salud Pblica,
CIBERESP). Madrid. Spain.
6. Unidad de Investigacin. Hospital Universitario
Donostia /Instituto de Investigacin Sanitaria Biodonostia,
Donostia REDISSEC.
7. Unidad de Investigacin. Hospital Universitario
Basurto, Bilbao / REDISSEC.
8. Servicio de Epidemiologa. Hospital Costa del
Sol, Mlaga REDISSEC.
9. Department of Preventive Medicine and Public
Health, Univesity of Valencia / CIBER de Epidemiologa y
Salud Pblica (CIBERESP) / CSISP-FISABIO, Valencia.
10. Unidad de Evaluacin de Tecnologas Sanitarias,
Agencia Lan Entralgo, Madrid.
11. Unidad Apoyo a Docencia-Investigacin.
Direccin Tcnica Docencia e Investigacin. Gerencia
Adjunta Planificacin. Gerencia de Atencin Primaria de
la Consejera de Sanidad de la Comunidad Autnoma de
Madrid.
12. Departamento de Matemtica Aplicada,
Estadstica e Investigacin Operativa, UPV- REDISSEC.
13. Epidemiologia Clnica y Cribado de Cancer,
Corporaci Sanitaria Parc Taul, Sabadell / REDISSEC.
14. Servicio de Oncologa. Hospital Universitario
Basurto, Bilbao.
15. Servicio de Ciruga General. Hospital
Universitario Basurto, Bilbao.
16. Servicio de Anatoma Patolgica. Hospital
Galdakao-Usansolo, Galdakao.
17. Servicio de Ciruga General. Hospital
Universitario Araba, Vitoria-Gasteiz.
18. Servicio de Gastroenterologa. Hospital
Universitario de Canarias, La Laguna.
19. Servicio de Ciruga General. Hospital Galdakao-
Usansolo, Galdakao.
20. IMAS-Hospital del Mar, Barcelona.
21. Servicio de Ciruga General y Digestiva.
Hospital Universitario Donostia.
22. Instituto de Investigacin Sanitaria Biodonostia,
Donostia.
23. Servicio de Ciruga General y Digestiva.
Hospital de Mendaro.
24. Servicio de Ciruga General y Digestiva.
Hospital de Zumrraga.
25. Servicio de Ciruga General y Digestiva.
Hospital del Bidasoa.
26. Servicio de Oncologa Mdica. Hospital
Universitario Donostia.
27. Instituto de Biomedicina de Sevilla. Hospital
Universitario Virgen del Roco, Sevilla.
28. Servicio de Ciruga. Hospital Universitario
Virgen de Valme, Sevilla.
29. Servicio de Ciruga General y Aparato Digestivo.
Hospital Dr. Pesset, Valencia.
30. Servicio de Ciruga General y Aparato Digestivo.
Agencia Sanitaria Costa del Sol, Marbella.
13 Oncotarget
 31. Servicio de Oncologa Mdica. Agencia
Sanitaria Costa del Sol, Marbella.
32. Servicio de Ciruga. Hospital de Antequera.
33. Coloproctology Unit, General and Digestive
Surgery Service, Corporaci Sanitaria Parc Taul,
Sabadell.
34. Digestive Diseases Department, Corporaci
Sanitaria Parc Taul, Sabadell.
35. Pathology Service, Corporaci Sanitaria Parc
Taul, Sabadell.
36. Medical Oncology Department, Corporaci
Sanitaria Parc Taul, Sabadell / REDISSEC.
37. General and Digestive Surgery Service, Parc de
Salut Mar, Barcelona.
38. General and Digestive Surgery Service, Althaia-
Xarxa Assistencial Universitaria, Manresa.
39. Catalonian Cancer Strategy Unit, Department of
Health, Institut Catal dOncologa.
40. Medical Oncology Department, Institut Catal
dOncologa.
41. Agency for Health Quality and Assessment of
Catalonia AquAS- and REDISSEC.
42. Agency for Health Quality and Assessment of
Catalonia AQuAS-, CIBER de Epidemiologa y Salud
Pblica CIBERESP.
43. Servicio de Ciruga General y del Aparato
Digestivo, Hospital Universitario Fundacin Alcorcn,
Madrid.
44. Servicio de Ciruga General y Aparato Digestivo,
Hospital Universitario Clnico San Carlos, Madrid.
45. Servicio Ciruga General y del Aparato
Digestivo, Hospital Universitario Infanta Sofa, San
Sebastin de los Reyes, Madrid.
46. Servicio de Ciruga General y del Aparato
Digestivo, Hospital Universitario La Paz, Madrid.
47. REDISSEC. Unidad de Apoyo a la Investigacin,
Gerencia de Atencin Primaria de Madrid, Madrid.
ACKNOWLEDGMENTS
This research was partially supported by grants from
REDISSEC (RD12/0001/0010), Fondo de Investigaciones
Sanitarias (13/0013) and Fondo Europeo de Desarrollo
Regional (FEDER).
CONFLICTS OF INTEREST
The authors declare no conflict of interest
Author contributions
MR, JMQ and IZ conceived the project. CS, NF, TT,
MB, collected all the data. FR and UA did the statistical
analyses. IZ wrote the first draft and revised drafts of the
manuscript. MR, JMQ, TT, MMMS-V, EB, AE, MB, AR
www.impactjournals.com/oncotarget
critically revised the manuscript for important intellectual
content.
The final version of the manuscript was approved
by all the authors.
MR, JMQ, MMMS-V, EB, NF, AE, AF, AR and
MB had full access to all of the data in the study and take
responsibility for the integrity of the data and the accuracy
of the data analysis. MR is the guarantor for the study
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